Journal of Medical Genetics最新文献

{"title":"Using long-read sequencing to detect and subtype a case with Temple syndrome.","authors":"Sarah Dada, Vahid Akbari, Duha Hejla, Yaoqing Shen, Katherine Dixon, Sanaa Choufani, Rosanna A Weksberg, Cornelius F Boerkoel, Laura Stewart, Kamilla Schlade-Bartusiak, Emma Strong, Danya Fox, Daniel Gamu, William T Gibson, Steven J M Jones","doi":"10.1136/jmg-2024-110262","DOIUrl":"https://doi.org/10.1136/jmg-2024-110262","url":null,"abstract":"<p><p>Temple syndrome is an imprinting disorder resulting from abnormal genomic or epigenomic aberrations of chromosome 14 including maternal uniparental disomy (matUPD), paternal deletion of 14q32, or aberrant methylation of the imprinting control regions at 14q32. Understanding the underlying molecular mechanism is essential to understanding the recurrence risk and physical effects. Currently, diagnosis requires the detection of aberrant methylation and copy number loss via methylation-sensitive assays such as methylation-specific multiplex ligation-dependent probe amplification, and short tandem repeat analysis to detect matUPD and the presence of epimutation. Therefore, a one-step approach that can detect aberrant methylation and underlying genetic mechanisms would be of high clinical value. Here we use nanopore sequencing to delineate the molecular diagnosis of a case with Temple syndrome. We demonstrate the application of nanopore sequencing to detect aberrant methylation and underlying genetic mechanisms simultaneously in this case, thus providing a proof of concept for a one-step approach for molecular diagnosis of this disorder.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>AOPEP</i>-related autosomal recessive dystonia: update on Zech-Boesch syndrome.","authors":"Sylvia Boesch, Michael Zech","doi":"10.1136/jmg-2025-110656","DOIUrl":"10.1136/jmg-2025-110656","url":null,"abstract":"<p><p>Gene discovery efforts have contributed to a better understanding of the molecular causes of dystonia, but knowledge of the individual monogenic forms remains limited. This review seeks to summarise all available data on the recently identified autosomal recessive subtype of dystonia caused by variants in <i>AOPEP</i>, focusing on the geographical origins of affected families, mutational spectrum, phenotypic expressions and pathophysiology. <i>AOPEP</i>-related dystonia, documented as Zech-Boesch syndrome in the Online Mendelian Inheritance in Man database, has been diagnosed in cohorts around the globe including under-represented populations with increased rates of consanguinity. Predictably leading to loss of protein function, the majority (74%) of disease-associated <i>AOPEP</i> alleles are protein-truncating variants comprising homozygous and compound heterozygous stop-gain, frameshift and splice-site changes. The dystonic disorder shows onset from childhood to the fourth decade and generalises in a significant proportion of cases (60%). Variable expressivity and age-related penetrance are likely to play a role in manifestation of the condition, consistent with occasional occurrence of <i>AOPEP</i> homozygous pathogenic variants in subjects without a diagnosis of dystonia. <i>AOPEP</i> encodes aminopeptidase O, a proteolytic processing enzyme that is preferentially expressed in glia and potentially linked to endosomal-lysosomal pathways. <i>AOPEP</i>-related autosomal recessive Zech-Boesch syndrome is of worldwide relevance for the diagnosis of genetic dystonia. Future research focusing on <i>AOPEP</i>`s role in cellular protein metabolism may provide new insights into dystonia pathogenesis and yet-unidentified therapeutic targets.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"388-395"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STIM1 in-frame deletion of eight amino acids in a patient with moderate tubular aggregate myopathy/Stormorken syndrome.","authors":"Emma Lafabrie, Maja Vrdoljak Pažur, Jocelyn Laporte, Johann Böhm","doi":"10.1136/jmg-2024-110273","DOIUrl":"10.1136/jmg-2024-110273","url":null,"abstract":"<p><p>Store-operated Ca²⁺ entry (SOCE) is a ubiquitous mechanism controlling Ca²⁺ homeostasis and relies on the reticular Ca²⁺ sensor STIM1 and the plasma membrane Ca²⁺ channel ORAI1. <i>STIM1</i> and <i>ORAI1</i> gain-of-function mutations induce excessive Ca²⁺ influx through SOCE overactivation and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterised by muscle weakness and additional signs such as short stature, thrombocytopenia and hyposplenism. Most patients carry missense mutations in the STIM1 Ca²⁺-sensing EF-hands or in the CC1 domain implicated in ORAI1 activation.Here we report the first STIM1 deletion in a patient with moderate TAM/STRMK phenotype encompassing exercise-induced muscle weakness, elevated creatine kinase levels, asplenia and transient thrombocytopenia. The c.702_725del mutation occurred de novo and is predicted to involve the deletion of eight amino acids between EF-hands and the CC1 domain. We conducted a series of functional experiments in mouse and human cells lines and provided the evidence that the in-frame deletion causes constitutive STIM1 clustering and ORAI1 recruitment, resulting in profuse extracellular Ca²⁺ entry and major nuclear translocation of the transcription factor NFAT1. Overall, this work illustrated the pathogenicity of the STIM1 in-frame deletion at different levels of the SOCE pathway and provided a molecular diagnosis for the affected family.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"381-387"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Very early-onset symptomatic CNS haemangioblastoma in Von Hippel-Lindau disease.","authors":"Marina Caballero, Vicente Santa-Maria Lopez, Laura Marti, Loreto Martorell, Diana Salinas, Jose Hinojosa, Maria Victoria Becerra, Miriam Pavon-Mengual, Andres Morales La Madrid, Ofelia Cruz, Jordi Muchart, Hector Salvador","doi":"10.1136/jmg-2024-110477","DOIUrl":"10.1136/jmg-2024-110477","url":null,"abstract":"<p><p>Von Hippel-Lindau disease is a genetic disorder characterised by the development of a variety of tumours and cysts, with central nervous system (CNS) haemangioblastoma being the most common manifestation. Early diagnosis through genetic counselling and surveillance is crucial for detecting asymptomatic stages of the disease to minimise morbidity and mortality associated with tumour complications and treatment interventions. In this report, we describe two cases of very early-onset symptomatic CNS haemangioblastoma and discuss the potential improvement in surveillance protocols by including both clinical and genetic factors.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"409-412"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Canadian College of Medical Geneticists (CCMG) position statement on the storage of patient genetic and genomic information in electronic health records.","authors":"Anne-Marie Laberge, Nolan D'Souza, Lynette S Penney, Karim Jessa, Lauren Chad","doi":"10.1136/jmg-2025-110629","DOIUrl":"https://doi.org/10.1136/jmg-2025-110629","url":null,"abstract":"<p><p>The aim of this document is to provide an updated statement from the Canadian College of Medical Geneticists (CCMG) regarding the current state and some future considerations on the collection, distribution, and storage of genomic information within electronic health records (EHRs), including which aspects of genomic data might warrant special attention. The original version of this document was written by the CCMG Ethics and Public Policy committee in 2010 based on data collected via an online survey of the CCMG membership at the time. It is updated here to reflect the current state of healthcare in 2024, where EHRs are almost ubiquitously used, and genomic medicine has expanded in its breadth and scope. The document was circulated to the general membership for review and feedback and has been approved by the CCMG Board of Directors.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical utility of genome sequencing in autism: illustrative examples from a genomic research study.","authors":"Thanuja Selvanayagam, Ny Hoang, Ege Sarikaya, Jennifer Howe, Carolyn Russell, Alana Iaboni, Morgan Quirbach, Christian R Marshall, Peter Szatmari, Evdokia Anagnostou, Jacob Vorstman, Dean M Hartley, Stephen W Scherer","doi":"10.1136/jmg-2024-110463","DOIUrl":"10.1136/jmg-2024-110463","url":null,"abstract":"<p><strong>Background: </strong>Genetics is an important contributor to autism spectrum disorder (ASD). Clinical guidelines endorse genetic testing in the medical workup of ASD, particularly tests that use whole genome sequencing (WGS) technology. While the clinical utility of genetic testing in ASD is demonstrated, the breadth of impact of results can depend on the variant and/or gene being reported.</p><p><strong>Methods: </strong>We reviewed research results returned to families enrolled in our ASD WGS study between 2012 and 2023. For significant results, we grouped the outcome of each genetic finding into three outcome categories: (1) genetic diagnosis, (2) counselling benefits and (3) support to family.</p><p><strong>Results: </strong>Out of 202 families who received genome sequencing results, 100 had at least one clinically relevant finding related to ASD. With detailed examples, we show that all significant results led to a genetic diagnosis and counselling benefits.</p><p><strong>Conclusion: </strong>Our findings show the relevance of genome sequencing in ASD and provide illustrative examples of how the information can be used.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"413-421"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12116238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicogenetic characterisation of SLC29A3-related syndromes: a case series, tracing ancestral variants and molecular dynamics simulation.","authors":"Sajjad Biglari, Mohammad Shahrooei, Fatemeh Vahidnezhad, Leila Youssefian, Vahid Ziaee, Nima Rezaei, Atefeh Sohanforooshan Moghaddam, Sahar Sedighzadeh, Hossein Moravej, Parisa Safari Foroushani, Majid Keivanfar, Homa Ilkhanipoor, Amir Hozhabrpour, Hooria Seyedhosseini-Ghaheh, Iraj Mohammadzadeh, Majid Naderi, Elham Sheikhi Ghayur, Nader Mansour Samaei, Saeed Dorgaleleh, Emran Esmaeilzadeh, Roya Sherkat, Hamid Reza Khorram Khorshid, Mohammad Amin Tabatabaiefar, Hakon Hakonarson, Hassan Vahidnezhad","doi":"10.1136/jmg-2024-110606","DOIUrl":"10.1136/jmg-2024-110606","url":null,"abstract":"<p><strong>Background: </strong>SLC29A3-related syndromes (SLC29A3-RS) are characterised by severe and multiorgan involvement that has a severe impact on the quality of life of the affected persons and therefore merit further genetic and clinical research. We investigated the clinical and genetic aspects of patients with SLC29A3-RS.</p><p><strong>Methods: </strong>Six pathogenic variants of the <i>SLC29A3</i> gene were identified in eight families in the current study. RNA sequencing was used for evaluating <i>SLC29A3</i> variant gene expression and protein stability by molecular dynamics (MD) simulations. This study conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review of cases across five electronic databases.</p><p><strong>Results: </strong>Genetic analysis revealed six pathogenic variants of the <i>SLC29A3</i> gene in eight families; one variant was shared among three families, indicating a possible founder effect. The estimated most recent common ancestor for these patients lived approximately 8.5 generations ago. MD studies revealed structural instability in mutant proteins. RNA sequencing also demonstrated that the expression of SLC29A3 was downregulated while the expression of the immune markers CD68 and LYZ was upregulated. A systematic search of 197 patients of different ethnic backgrounds revealed that the following symptoms were frequent findings: hyperpigmentation, hypertrichosis, hearing loss, short stature and hepatomegaly. The age of onset of SLC29A3-RS was 5.53±5.24 years with an IQR of 1.4-8.25 years.</p><p><strong>Conclusions: </strong>The characterisation of the founder variants and the genotype-phenotype correlations helps delineate the phenotype spectrum of SLC29A3-RS, which will facilitate the genetic counselling and screening of the high-risk population. Findings on <i>SLC29A3</i> variants show the way to proceed in the process of developing the diagnostic and therapeutic methods in the management of SLC29A3-RS.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"369-380"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysing tumours for genetic diagnosis in mosaic neurofibromatosis type 1.","authors":"Tabea Isabelle Hartung, Lan Kluwe, Said Chosro Farschtschi","doi":"10.1136/jmg-2024-110580","DOIUrl":"10.1136/jmg-2024-110580","url":null,"abstract":"<p><p>Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disorder caused by pathogenic variants in the <i>NF1</i> gene, resulting in diverse clinical manifestations, especially multiple cutaneous neurofibromas. In approximately 50% of cases, variants occur de novo, and a portion of these cases involves genetic mosaicism, where variants are present in a subset of cells of an individual. Mosaic NF1 often presents with a milder phenotype and reduced transmission risk, complicating clinical diagnosis and genetic consulting. Conventional blood-based genetic testing may fail to detect the pathogenic variants in mosaic cases, necessitating additional analysis using tumour-derived DNA. We present five such cases and suggest a comprehensive diagnostic workflow focusing on tumour-based analysis for mosaic cases.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"405-408"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De novo heterozygous missense variants in <i>ATP11A</i> are associated with refractory focal epilepsy.","authors":"Zi-Long Ye, Nan-Xiang Shen, Xiang-Yun Luo, Hai-Sheng Lin, Yu-Tao Guo, Dong-Jie Qiu, Shi-Zhan Yuan, Ming-Feng He, Cui-Xia Fan, Wen-Bin Li, Yi-Wu Shi, Li-Bin Zhang","doi":"10.1136/jmg-2024-110540","DOIUrl":"10.1136/jmg-2024-110540","url":null,"abstract":"<p><strong>Background: </strong><i>ATP11A</i> encodes an integral-membrane type IV P-type-adenosine triphosphatase that plays an important role in neural development by maintaining membrane lipid asymmetry. <i>ATP11A</i> de novo heterozygous missense variants have been reported to be associated with hypomyelinating leukodystrophy; however, the neurological symptoms of patients are often varying. In this study, we aimed to explore the relationship between <i>ATP11A</i> variants and epilepsy.</p><p><strong>Methods: </strong>Trio-based whole-exome sequencing was performed on patients with focal epilepsy. Multiple bioinformatics analyses were used to predict the pathogenicity of the variants. Previously reported literature was collected to analyse the relation between variants and phenotypes.</p><p><strong>Results: </strong>Two de novo heterozygous missense variants of <i>ATP11A</i> were identified in two unrelated patients with refractory focal epilepsy and were predicted to be pathogenic using multiple bioinformatics analyses. Then, six patients associated with missense variants were collected. Half of the patients (3/6) with variants located on/near the transmembrane regions (TMs) had more severe and multiple neurological symptoms, while the other half with non-TM variants had mild and single symptoms, indicating a correlation between variant location and phenotype. All patients showed progressively worsening conditions, potentially due to a gradually increased expression of <i>ATP11A</i> in the human brain over time.</p><p><strong>Conclusion: </strong>This study suggested that de novo heterozygous missense variants of <i>ATP11A</i> are associated with refractory focal epilepsy. Missense variant-associated phenotypes range from epileptic seizures to severe neurological symptoms. It should be noted that patients with <i>ATP11A</i> variants have a gradually worsening potential.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":" ","pages":"396-404"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Six at Sixty. Commentary on osteogenesis imperfecta 1975-2025.","authors":"David Sillence","doi":"10.1136/jmg-2025-110807","DOIUrl":"https://doi.org/10.1136/jmg-2025-110807","url":null,"abstract":"<p><p>Between 1975 and 1977, my collaborators and I conducted a whole-of-population study in Victoria, Australia, examining the various presentations and clinical manifestations of osteogenesis imperfecta (OI) and familial forms of bone fragility. In 1975, the prevailing view was that all presentations of OI reflected variable expression of pathogenic genomic variants at a single gene locus-possibly involving the recently identified protein, type I collagen. We concluded that OI was in fact genetically heterogeneous, setting the scene for future biochemical and genomic discoveries. Currently, OI is recognised to result from pathological variants in >20 genes, with variants in many further loci resulting in related forms of familial osteoporosis or special syndromes characterised by bone fragility. A dyadic nosology has been adopted to help clinicians, researchers and affected individuals in accessing OI diagnosis, treatment and research with a focus on precision medicine.</p>","PeriodicalId":16237,"journal":{"name":"Journal of Medical Genetics","volume":"62 6","pages":"422-426"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}